Multiple myeloma is a neoplasia of plasma cells in the bone marrow and is presently an incurable disease. However recent advances have been made including the successful use of the proteasome inhibitor, bortezomib (Velcade) in refractory and relapsed myeloma. While initially believed to kill cells through inhibition of NF-?B, re-evaluation of previous data as well as data presented within suggest that while inhibition of NF-?B may play a role in proteasome inhibitor induced cell death, it is unlikely to be the primary factor that determines myeloma cell sensitivity. We believe that the sensitivity of the myeloma cell lies with the function of its normal counterpart, the plasma cell. Plasma cells possess a complex endoplasmic reticulum to assure proper folding and assembly of antibodies. This is due to the activation of the physiologic component of the unfolded protein response (UPR) during plasma cell development. We hypothesize that plasma cells and by extension myeloma cells are highly susceptible to additional ER stress and that proteasome inhibition induces apoptosis in myeloma through inhibition of the retrograde translocation of misfolded/damaged proteins from the ER to the cytoplasm. This results in the accumulation of proteins in the ER and the activation of the terminal components of the UPR. We propose three specific aims to determine the role of the UPR and ER stress in proteasome inhibitor-induced apoptosis in myeloma cells. We have demonstrated that proteasome inhibition results in the activation of the terminal components of the UPR therefore in the first specific aim, we will determine the role of the UPR in proteasome inhibitor sensitivity. In the second specific aim we will focus on the role of endoplasmic reticulum associated degradation (ERAD) in proteasome inhibitor induced apoptosis. Finally it is not clear how ER stress results in the activation of an apoptotic program. We have published that neither caspase-12 nor caspase-4 are necessary for ER stress-induced apoptosis. Therefore in the third aim we will take a systematic approach to determine the mechanism of proteasome inhibitor initiated ER stress-induced apoptosis. Understanding the mechanism(s) that result in sensitivity to proteasome inhibitor-induced apoptosis will likely provide rationale for the use of this class of agents in other cancers of highly specialized secretory cells as well as provide additional targets for therapy within the ER pathway for myeloma.